In South Africa, where it is estimated that more people have HIV than anywhere else in the world and where many women trade sex in order to survive, targeted evidence-based strategies to reach vulnerable populations of women are essential. To address the objectives of RFA-DA11-001, we propose to (1) expand HIV testing to reach more at-risk women so that HIV-positive women can be evaluated to be placed and retained on antiretroviral therapy (ART), (2) assess sustainable woman-focused prevention practices for both HIV-positive and HIV-negative alcohol and other drug (AOD)-using women, and (3) measure the effectiveness of a combined prevention strategy on ART initiation, adherence, retention, and reduced risk behavior. Our proposed partner, the Foundation for Professional Development (FPD), is one of the largest PEPFAR-funded operational programs in South Africa. FPD is responsible for a medical management program supporting 90,000 patients on ART across the country. However, FPD does not currently target and reach vulnerable AOD-using women, detecting only 8.5% HIV positive compared with our previous study in the same region reaching vulnerable AOD-using women, with an estimated HIV prevalence of 65% among sex workers and 26% among non-sex workers. Based on this critical need to reach some of the most vulnerable South African women, we propose to combine our capabilities, in collaboration with scientific and medical expertise from the UNC Center for AIDS Research, to provide a combination prevention approach that optimizes the test, treat, and retain (TTR) strategy to reach high-risk, vulnerable, AOD-using women. We will use a geographically clustered randomized design to compare the Women's Health CoOp (WHC) outreach and intervention program - a proven woman-focused enhanced HIV prevention strategy that addresses AOD use, and sex risk behaviors, gender-based violence, empowerment, skills training, and personalized action plans for both HIV-positive and HIV-negative women - plus voluntary counseling and testing (VCT), with VCT alone as standard practice. Targeting most-at-risk women who use AODs, who have multiple partners, and who have poor condom practices, will also impact their other partners and thus the wider community. The overarching goal of the proposed research is to determine whether this combined prevention and enhanced strategy targeting a specific at-risk group is more effective than current standard practices. The proposed combination prevention intervention is designed specifically to reach more at-risk vulnerable AOD-using women and be tested in an existing implementation program. If this combination woman-focused prevention intervention proves efficacious, there is a high likelihood that it can be widely implemented and have a substantial public health impact by reducing the exceedingly high HIV incidence in South Africa. PUBLIC HEALTH RELEVANCE: There is growing recognition that no single strategy will be sufficient to eliminate HIV transmission. In light of evidence that neither existing biomedical interventions nor any existing behavioral interventions will be sufficient to control the HIV epidemic in South Africa, the proposed study will combine a biomedical intervention (i.e., testing, treating, retention) with an evidence-based behavioral intervention (i.e., the Women's Health CoOp) to maximize the efficacy of both strategies. The proposed combination prevention intervention is designed specifically to reach more at-risk vulnerable alcohol and other (AOD) drug using women and be tested in an existing implementation program. If this combination intervention proves efficacious, there is a high likelihood that it can be widely implemented, be sustainable and have a substantial public health impact by reducing the exceedingly high HIV incidence in South Africa.